Aryloxy alkanols as anti-retrovirus agents

ABSTRACT

Aryloxyalkanol derivatives having the formula 
     
         Ar--O(CH.sub.2).sub.n OH 
    
     wherein n is an integer from 3 to 8 and Ar is (1) 1- or 2-naphthylenyl, (2) phenyl optionally substituted by from 1 to 3 C 1-4  lower alkyl groups, or (3) a diphenyl moiety of structure ##STR1## wherein Y is a bond, CH 2  or CH 2  O, and esters thereof have antiretrovirus activity and are effective in a method for treatment of a retrovirus infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 284,146, filed Dec. 14,1988, U.S. Pat. No. 4,939,173, July 3, 1990.

FIELD OF INVENTION

The present invention relates to the use of certain aryloxyalkanols andesters thereof with pharmaceutically acceptable acids in the treatmentof retroviral infections including HIV infections.

BACKGROUND OF THE INVENTION

A great deal of research is currently underway to develop treatments andcures for viral infections in humans and in animals. Notably theincidence of acquired immune deficiency syndrome (AIDS) and AIDS relatedcomplex (ARC) in humans is increasing at an alarming rate. The five yearsurvival rate for those with AIDS is dispiriting and AIDS patients,whose immune systems have been seriously impaired by the infection,suffer from numerous opportunistic infections including Kaposi's sarcomaand Pneumocystis carninii pneumonia. No cure is known and currenttreatments are largely without adequate proof of efficacy and havenumerous untoward side effects. Fear of the disease has resulted insocial ostracism of and discrimination against those having or suspectedof having the disease.

Retroviruses are a class of ribonucleic acid (RNA) viruses thatreplicate by using reverse transcriptase to form a strand ofcomplementary DNA (cDNA) from which a double stranded, proviral DNA isproduced. This proviral DNA is then randomly incorporated into thechromosomal DNA of the host cell. Further transcription and translationof the integrated viral genome DNA results in viral replication throughthe synthesis of virus specific RNA and proteins.

Many of the known retroviruses are oncogenic or tumor causing. Indeedthe first two human retroviruses discovered, denoted human T-cellleukemia virus I and II or HTLV-I and II, were found to cause rareleukemias in humans after infection of T-lymphocytes. The third suchhuman virus to be discovered, HTLV-III, now referred to as HIV, wasfound to cause cell death after infection of T-lymphocytes and has beenidentified as the causative agent of acquired immune deficiency syndrome(AIDS) and AIDS related complex (ARC).

Among the substances previously shown to have activity against HIV andother retroviruses are such diverse compounds as azidothymidine,castanospermine, and heparin.

The applicants have now discovered that certain aryloxyalkanols, morespecifically certain naphthylenyl, biphenylyl, benzylphenyl,benzyloxyphenyl, and substituted and unsubstituted phenyl ethers of C₃₋₈straight-chain α,ω-glycols, esters thereof with pharmaceuticallyacceptable acids, and the salts thereof, are useful in the treatment ofvarious retroviral infections including in the treatment of AIDS and ARCresulting from infection by HIV or other retroviruses.

SUMMARY OF THE INVENTION

The anti-retrovirus aryloxyalkanols of this invention have the generalFormula I

    Ar--O(CH.sub.2).sub.n OH

    I

wherein n is an integer from 3 to 8 and Ar is (1) 1- or

2-naphthylenyl, (2) phenyl optionally substituted by from 1 to 3 C₁₋₄lower alkyl groups, or (3) a diphenyl moiety of structure ##STR2##wherein Y is a bond, CH₂ or CH₂ O.

The use as anti-retroviral agents of esters of compounds of Formula Iwith pharmaceutically acceptable acids and salts of said esters is alsoincluded within the scope of this invention.

Many compounds of Formula I are known in the prior art, and the use ofsome of these compounds for treatment and prophylaxis of infection hasbeen described in British patent 2,068,952, but their usefulness intreatment of diseases caused by infection with a retrovirus has nothitherto been known.

DETAILED DESCRIPTION OF THE INVENTION

When Ar represents naphthylenyl, the hydroxyalkoxy group may be in the1- or 2- position of the naphthylene moiety. When Ar representssubstituted phenyl, the substituents are straight- or branched-chainalkyl group having from 1 to 4 carbon atoms. The alkyl groups areexemplified by methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl. The preferred alkyl substituent is methyl. Thealkyl substituents may be in the ortho, meta or para positions relativeto the hydroxyalkoxy chain and, when 2 or 3 alkyl groups are present, toone another.

In the compounds of Formula I wherein Ar represents, a diphenyl moietyof structure ##STR3## substituent Y may be disposed ortho, meta or parato the hydroxyalkoxy chain on the benzene ring common to both,preferably meta or para, and most preferably in the para orientation.

The linear, saturated carbon chain linking the ether with the hydroxylgroup may range in length from 3 to 8 carbon atoms. Compounds having achain length of 6 methylene units are preferred.

Esters of the compounds of Formula I with pharmaceutically acceptableacids also show anti-retrovirus activity. The alcohols are oftendifficulty soluble in water. Esterification with a solubilizingpharmaceutically acceptable acid, preferably a polycarboxylic acid,increases water solubility and facilitates absorption of the compound.Particularly desirable esters include monoesters of polycarboxylic acidsand/or the salts of such monoesters, preferably sodium salts.

Suitable esters include esters of alkanoic, alkenoic, alkenedioic andalkanedioic acids having from 1 to 4 carbon atoms, for example, acetic,butyric, malonic, maleic, succinic, and fumaric acids. Esters of theseacids and the alkanols of Formula I are prepared by methods well knownto the art. For example, maleates and succinates are convenientlyprepared by reacting the compound with maleic or succinic anhydride inpyridine, followed by acidification and isolation of the monoester.

Illustrative compounds of this invention are:

6-phenoxyhexan-1-ol,

6-(2,4,6-trimethylphenoxy)hexan-1-ol,

6-(4-phenylphenoxy)hexan-1-ol,

6-(4-benzylphenoxy)hexan-1-ol,

6-(4-benzyloxyphenoxy)hexan-1-ol

6-(2-naphthylenyloxy)hexan-1-ol.

Also included are compounds analogous to each of the foregoing havinganother unbranched alkylene chain of from 3 to 8 carbon atoms in placeof the hexamethylene chain, e.g., 3-(4-phenylphenoxy)propan-1-ol through8-(4-phenylphenoxy) octan-1-ol, and the corresponding alcohols in eachseries above.

Included also are isomers of each of the foregoing compounds having thehydroxyalkoxy group and Y meta or ortho to one another on the centralbenzene ring common to both, e.g., 6-(3-benzyloxyphenoxy)hexan-1-ol,6-(2-phenylphenoxy)-hexan-1-ol, and the corresponding ortho and metaisomers of each of the compounds hereinabove.

Also included are pharmaceutically acceptable esters of each of theabove alcohols with various acids, more specifically, monoesters withmaleic, succinic, fumaric, and acetic acids.

The ability of the aryloxyalkanol derivatives of this invention to actas anti-retroviral agents can be demonstrated by their ability toinhibit the growth and replication of murine leukemia virus, anoncogenic retrovirus, as determined by an in vitro XC plaque assay. Thisassay was performed according to the method of Rowe et al. (Virology,1970, 42, 1136-39) as previously described by L. Hsu, et al. (J.Viroloqical Methods, 1980, 1, 167-77) and T. L. Bowlin and M. R.Proffitt (J. Interferon Res., 1983, 3(1), 19-31). Mouse SC-1 cells(fibroblast) (10⁵) were seeded into each well of 6-well cluster plates(Costar #3506) in 4 ml Minimum Essential Medium (MEM) with 10% FetalCalf Serum (FCS). Following an 18 hour incubation period (37° C.),Moloney murine leukemia virus (MoLV) was applied at a predeterminedtiter to give optimal (i.e. countable) numbers of virus plaques.Compounds were added 2 hours prior to addition of the virus. Three dayslater the culture medium was removed, the SC-1 cell monolayers wereexposed to UV irradiation (1800 ergs), and rat XC cells (10⁶) wereseeded into each well in 4 ml MEM. Following an additional 3 dayincubation (37° C.), these cells were fixed with ethyl alcohol (95%) andstained with 0.3% crystal violet. Plaques were then counted under lowmagnification. The antiviral activities of various compounds of thisinvention are tabulated in Table I in terms of the IC₅₀, i,e, theconcentration giving a 50% inhibition of virus plaque growth.

                  TABLE 1                                                         ______________________________________                                        INHIBITORY CONCENTRATION OF VARIOUS                                           ARYLOXYALKANOL DERIVATIVES OF FORMULA I                                       AGAINST MURINE LEUKEMIA VIRUS                                                                                     IC50                                      Compound        Ar            n     (μg/ml)                                ______________________________________                                        6-Phenoxyhexan-1-ol                                                                           Phenyl        6     1                                         6-(2,4,6-Trimethyl-                                                                           2,4,6-Trimethyl-                                                                            6     5                                         phenoxy)hexan-1-ol                                                                            phenyl                                                        6-(4-Phenylphenoxy)-                                                                          4-Phenylphenyl                                                                              6     2.5-5                                     hexan-1-ol                                                                    6-(4-Phenylphenoxy)hexyl                                                                      4-Phenylphenyl                                                                              6     1-10                                      succinate monoester                                                           6-(4-Benzylphenoxy)-                                                                          4-Benzylphenyl                                                                              6     1-10                                      hexan-1-ol                                                                    4-(4-Benzyloxyphenoxy)-                                                                       4-Benzyloxyphenyl                                                                           4     1-10                                      butan-1-ol                                                                    6-(4-Benzyloxyphenoxy)-                                                                       4-Benzyloxyphenyl                                                                           6     1-10                                      hexan-1-ol                                                                    6-(2-Naphthylenyloxy)-                                                                        2-Naphthylenyl                                                                              6     5-10                                      hexan-1-ol                                                                    ______________________________________                                    

To further confirm the antiretroviral activity of these compounds,6-(4-phenylphenoxy)hexan-1-ol was evaluated for activity against HIV.Following overnight pretreatment of T-cells (JM cells) with the HIV1GB8strain of HIV-1, 6-(4-phenylphenoxy)hexan-1-ol was added to the cellcultures at concentrations of 15 and 7.5 μg/ml. After 4 days the thenumber of synctial cells in the cell culture and the amount of p24antigen, also a measure of viral replication, were determined. The dataare shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        ANTI-HIV ACTIVITY OF                                                          6-(4-PHENYLPHENOXY)HEXAN-1-OL                                                                                   P24                                                   SYNCYTIAL   %           ANTIGEN                                     TREATMENT COUNT       INHIBITION  pg × 10.sup.3 /ml                     ______________________________________                                        Untreated 29          --          801                                         6-(4-Phenyl-                                                                            0           100          62                                         phenoxy)hexan-                                                                1-ol, 15 μg/ml                                                             6-(4-Phenyl-                                                                            8            72         Not                                         phenoxy)hexan-                    determined                                  1-ol, 7.5 μg/ml                                                            ______________________________________                                    

The aryloxyalkanol derivatives of this invention can be used to treat anumber of diseases and conditions known to be caused by retrovirusesincluding those diseases and conditions caused by murine leukemia virus,feline leukemia virus, avian sarcoma virus, human immunodeficiency virus(HIV), HTLV-I, and HTLV-II. Those experienced in this field are readilyaware of the circumstances requiring anti-retroviral therapy. Applicantsconsider the use of the aryloxyalkanol derivatives of this invention totreat HIV infections in humans to be of most importance. The term"patient" used herein is taken to mean mammals such as primates,including humans, sheep, horses, cattle, pigs, dogs, cats, rats andmice, and birds.

The amount of the aryloxyalkanol derivative of formula I to beadministered can vary widely according to the particular dosage unitemployed, the period of treatment, the age and sex of the patienttreated, the nature and extent of the disorder treated, and theparticular aryloxyalkanol derivative selected. Moreover thearyloxyalkanol derivative can be used in conjunction with other agentsknown to be useful in the treatment of retroviral diseases and agentsknown to be useful to treat the symptoms of and complications associatedwith diseases and conditions caused by retroviruses. Theantiretrovirally effective amount of an aryloxyalkanol derivative offormula I to be administered will generally range from about 15 mg/kg to500 mg/kg. A unit dosage may contain from 25 to 500 mg of thearyloxyalkanol derivative, and can be taken one or more times per day.The aryloxyalkanol derivative can be administered with a pharmaceuticalcarrier using conventional dosage unit forms either orally orparenterally.

The preferred route of administration is oral administration. For oraladministration the aryloxyalkanol derivative can be formulated intosolid or liquid preparations such as capsules, pills, tablets, troches,lozenges, melts, powders, solutions, suspensions or emulsions. The solidunit dosage forms can be capsules, which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate and cornstarch. In another embodiment the compounds of thisinvention can be tableted with conventional tablet bases such aslactose, sucrose, and cornstarch in combination with binders such asacacia, cornstarch, or gelatin, disintegrating agents intended to assistthe break-up and dissolution of the tablet following administration,such as potato starch, alginic acid, corn starch and guar gum,lubricants intended to improve the flow of tablet granulations and toprevent the adhesion of tablet material to the surfaces of the tabletdies and punches, for example, talc, stearic acid, or magnesium, calciumor zinc stearate, dyes, coloring agents, and flavoring agents intendedto enhance the aesthetic qualities of the tablets and make them moreacceptable to the patient. Suitable excipients for use in oral liquiddosage forms include diluents such as water and alcohols, for example,ethanol, benzyl alcohol, and the polyethylene alcohols, either with orwithout the addition of a pharmaceutically acceptably surfactant,suspending agent, or emulsifying agent.

The aryloxyalkanol derivatives of this invention may also beadministered parenterally, that is, subcutaneously, intravenously,intramuscularly or interperitoneally, as injectable dosages of thecompound in a physiologically acceptable diluent with a pharmaceuticalcarrier which can be a sterile liquid or mixture of liquids such aswater, saline, aqueous dextrose and related sugar solutions, an alcoholsuch as ethanol, isopropanol or hexadecyl alcohol, glycols such aspropylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl1,3-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, oran acetylated fatty acid glyceride, with or without the addition of apharmaceutically acceptable surfactant such as a soap or a detergent, asuspending agent such as pectin, carbomers, methylcellulose,hydroxypropylmethylcellulose or carboxymethylcellulose, or anemulsifying agent, and other pharmaceutical adjuvants. Illustrative ofoils which can be used in the parenteral formulations of this inventionare those of petroleum, animal, vegetable, and synthetic origin, forexample, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil,olive oil, petrolatum, and mineral oil. Suitable fatty acids includeoleic acid, stearic acid, and isostearic acid. Suitable fatty acidesters are, for example, ethyl oleate and isopropyl myristate. Suitablesoaps include fatty alkali metal, ammonium, and triethanolamine saltsand suitable detergents include cationic detergents, for example,dimethyl dialkyl ammonium halides, alkyl pyridinium halides, andalkylamine acetates; anionic detergents, for example, alkyl, aryl, andolefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, andsulfosuccinates; nonionic detergents, for example, fatty amine oxides,fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers;and amphoteric detergents, for example, alkyl β-aminopropionates and2-alkylimidazoline quarternary ammonium salts, as well as mixtures. Theparenteral compositions of this invention will typically contain fromabout 0.5 to about 25% by weight of the aryloxyalkancl derivative offormula 1 in solution. Preservatives and buffers may also be usedadvantageously. In order to minimize or eliminate irritation at the siteof injection, such compositions may contain a non-ionic surfactanthaving a hydrophile-lipophile balance (HLB) of from about 12 to about17. The quantity of surfactant in such formulations ranges from about 5to about 15% by weight. The surfactant can be a single component havingthe above HLB or can be a mixture of two or more components having thedesired HLB. Illustrative of surfactants used in parenteral formulationsare the class of polyethylene sorbitan fatty acid esters, for example,sorbitan monooleate and the high molecular weight adducts of ethyleneoxide with a hydrophobic base, formed by the condensation of propyleneoxide with propylene glycol.

The compounds of Formula I are generally prepared by Williamson ethersynthesis (J. March, "Advanced Organic Chemistry--Reactions, Mechanismsand Structure," McGraw-Hill Book Company, New York, 1968, p. 316). Thereaction is illustrated in the following reaction scheme: ##STR4##

In the above reaction sequence, L represents a halogen atom, such aschlorine, bromine or iodine, or a sulfonate ester such asmethanesulfonate or p-toluenesulfonate; M⁺ represents a metal ion suchas lithium, sodium, potassium, silver or mercury; and Ar and n are asdefined for Formula I.

A phenoxide or naphthoxide salt, represented by structure II andconveniently formed in situ by addition of a base such as sodiummethoxide, potassium carbonate, sodium hydride or potassium hydroxide tothe corresponding phenol or naphthol, is reacted with an alcohol bearinga leaving group on the terminal carbon atom, and having the structureIII. The leaving group is displaced, resulting in the formation of acarbon-oxygen ether bond.

The starting naphthols and phenols which are the precursors of thenaphthoxide and phenoxide salts are generally commercially available orare available by entirely conventional synthetic methods well-known inthe art. For example, benzyloxyphenols can be prepared by reaction ofbenzyl halides with hydroquinones or resorcinols, or with theirmonoesters, with subsequent hydrolysis.

The benzylphenols are readily prepared by reduction of the correspondinghydroxybenzophenones. The latter are prepared, for example, byFriedel-Crafts benzoylation of phenyl acetate, by Fries rearrangement ofphenyl benzoates, or by oxidation of benzhydryl alcohols.

Phenylphenol may be prepared by the Ullmann reaction of a phenoxide anda halophenyl ester, in the presence of copper salts. See March,"Advanced Organic Chemistry," pages 500-508 (McGraw-Hill, New York,1968).

The ω-substituted linear alcohols, III, used in the sequence are alsogenerally available commercially or by well-known, conventionalsynthetic methods. For example, the α,ω-diol may be converted to the-haloalcohol using triphenylphosphine and carbon tetrahalide (see C.A.,63, 13137c (1965) for the preparation of 12-bromododecane-1-ol).

The Williamson reaction may be carried out with or without solvents.Suitable solvents for the reaction incude lower alcohols, such asethanol and isopropanol, ketones such as acetone and butanone, or amidessuch as dimethylformamide and dimethylacetamide. Other suitable solventsinclude dimethylsulfoxide, acetonitrile, dimethoxyethane,tetrahydrofuran and toluene.

The temperature of the reaction may vary from about 0° C. to the refluxtemperature of the solvent, and the reaction time may vary from about0.5 hour to 80 hours.

The reaction is conveniently worked up by extraction of the product intoan organic solvent such as ether, dichloromethane, chloroform, tolueneor the like, washing with brine, drying over sodium or magnesiumsulfate, and evaporation of the solvent. Purification is generallyeffected by distillation or crystallization from a suitable solvent.

Esters of compounds of Formula I are formed by conventional methods,such as reaction of the alcohol of Formula I with an acid, an acidhalide, an anhydride, or other activated acyl derivative, often in thepresence of an acid acceptor. The product is isolated in a conventionalfashion and purified by distillation or crystallization from anappropriate solvent. Salts of monesters of polybasic acids are preparedby addition of base, e.g., NaH, to an ether solution of the ester,followed by filtration of the resultant precipitate.

EXAMPLE I 6-(4-Phenylphenoxy)hexan-1-ol

A mixture of 34.0 g (0.2 mole) or p-phenylphenol (Eastman) and 10.8 g(0.2 mole) of sodium methoxide (MCB) in 500 ml of dry dimethylformamideis heated and stirred on a steam bath for 0.5 hour, after which 27.3 g(0.2 mole) of 6-chlorohexan-1-ol (MCB) and about 2 g of sodium iodideare added. The mixture is heated to reflux with stirring, and thenallowed to cool to room temperature. The reaction mixture is partitionedbetween ether/acetone and water, and the organic phase is extracted withbase, washed with water and brine, dried (Na₂ SO₄), and the solventevaporated. The resultant white solid product is recrystallized twicefrom methanol/acetone, to give the desired product, m.p. 103°-105° C.

EXAMPLE 2 6-(4-Benzyloxyphenoxy)hexan-1-ol

A mixture of 106.0 g (0.53 mole) of p-benzyloxyphenol (Eastman), 28.6 g(0.53 mole) sodium methoxide (MCB) and about 2 g of sodium iodide in 600ml of dimethylformamide is stirred for 5 minutes, after which 73 g (0.53mole) of 6-chlorohexan-1-ol (MCB) is added, and the mixture is refluxedwith stirring. The methanol formed in the reaction is allowed to distilloff. After 2 hours reflux, the mixture is diluted with ice and water,500 ml of 10% potassium hydroxide is added, and the resultantprecipitate collected and dried. The solid is combined with 1 liter ofbutanone, refluxed and filtered. The residue is cooled, whereupon thedesired product crystallizes out. The solid product is stirred with 1liter of acetone at room temperature, the mixture is filtered toseparate additional insoluble byproduct, the acetone boiled off andreplaced with methanol, and the methanolic solution cooled tocrystallize out the desired product, m.p. 94°-97° C.

EXAMPLE 3 6-(4-Benzylphenoxy)hexan-1-ol

A mixture of 40.0 g (0.217 mole) of p-benzylphenol (Eastman) and 29.7 g(0.217 mole) of 6-chlorohexan-1-ol (MCB) in 500 ml of drydimethylformamide is stirred and heated to about 100° C., after which33.1 g (0.24 mole) of potassium carbonate is added, and the mixturerefluxed for 2.5 hours. The mixture is cooled, poured into ice-water,and 50 ml of 10% NaOH is added. The mixture is extracted with ether, theether extracts washed with water and brine, dried (Mg₂ SO₄), and theether evaporated. The resultant oil is redistilled to give the productas a water-white oil fraction distilling at 140°-175° C., 0.05 mmHg.

EXAMPLE 4 6-(3-Phenylphenoxy)hexan-1-ol

A mixture of 15.0 g (0.088 mole) of 3-hydroxybiphenyl, 13.3 g (0.097mole) of 6-chlorohexan-1-ol, and 13.8 g (0.01 mole) of potassiumcarbonate in 250 ml of dry dimethylformamide is stirred and heated toreflux for 3 hours. The mixture is cooled to room temperature, dilutedwith water, and extracted with ether, the ether extracts dried andevaported under reduced pressure to give a light yellow oil. The crudeproduct is vacuum distilled to give a fraction boiling between 150° and190° C. (0.05 mmHg), and solidifying to a soft solid, corresponding tothe pure desired product.

EXAMPLE 5

Using the procedure of Example 2, the following phenolic compounds maybe reacted with the indicated haloalcohols to produce the compoundsshown below (Ph=phenyl):

    __________________________________________________________________________    Phenol        Haloalcohol                                                                              Product             M.P. (°C.)                __________________________________________________________________________    p-Ph--Ph--OH  4-Cl--(CH.sub.2).sub.4 --OH                                                              p-Ph--Ph--O--(CH.sub.2).sub.4 --OH                                                                110-113°                  p-Ph--Ph--OH  5-Cl--(CH.sub.2).sub.5 --OH                                                              p-Ph--Ph--O--(CH.sub.2).sub.5 --OH                                                                108-109°                  p-Ph--Ph--OH  8-Cl--(CH.sub.2).sub.8 --OH                                                              p-Ph--Ph--O--(CH.sub.2).sub.8 --OH                                                                103-106°                  p-(Ph--CH.sub.2 --O)--Ph--OH                                                                4-Cl--(CH.sub.2).sub.4 --OH                                                              p-(Ph--CH.sub.2 --O)--Ph--O--(CH.sub.2).sub.4                                 --OH                97-99°                    p-(Ph--CH.sub.2 --O)--Ph--OH                                                                5-Cl--(CH.sub.2).sub.5 --OH                                                              p-(Ph--CH.sub.2 --O)--Ph--O--(CH.sub.2).sub.5                                 --OH                90-93°                    __________________________________________________________________________

EXAMPLE 6 6-[4-Phenylphenoxy)-1-hexyl succinate (monoester)

A mixture of 10 g (0.037 mole) of 6-(4-phenylphenoxy) hexan-1-ol,prepared in Example 1, and 10 g of succinic anhydride in 250 ml ofpyridine is refluxed with stirring for 3 hours. The pyridine is removedunder vacuum on a steam bath, the residue poured into water andacidified with HCl. The resultant precipitate is collected, washed,dried and recrystallized from butanone, to give the pure monoester, m.p.113°-115° C.

EXAMPLE 7 Solution

    ______________________________________                                        Solution                                                                      ______________________________________                                        6-(4-Phenylphenoxy)hexan-1-ol                                                                           0.85   g                                            Alcohol                   78.9   ml                                           Isopropyl Myristate       5.0    g                                            Polyethylene Glycol 400 (Av. M.W. 400)                                                                  10.0   g                                            Purified Water sufficient to make                                                                       100    ml                                           ______________________________________                                    

Combine the alcohol, isopropyl myristate and polyethylene glycol 400 anddissolve the drug substance therein. Add sufficient purified water togive 100 ml.

EXAMPLE 8

    ______________________________________                                        Tablet                                                                                              For 15,000                                              ______________________________________                                        6-(4-Benzyloxyphenoxy)hexan-1-ol                                                                      75     g                                              Lactose                 1.216  kg                                             Corn Starch             03.    kg                                             ______________________________________                                    

Mix the active ingredient, the lactose and corn starch uniformly.Granulate with 10% starch paste. Dry to a moisture content of about2.5%. Screen through a No. 12 mesh screen. Add and mix the following:

    ______________________________________                                        Magnesium               0.015  kg                                             Corn Starch sufficient to make                                                                        1.725  kg                                             ______________________________________                                    

Compress on a suitable tablet machine to a weight of 0.115 g/tablet.

EXAMPLE 9 Soft Gelatin Capsule

    ______________________________________                                        Soft Gelatin Capsule                                                          ______________________________________                                        6-(4-Phenylphenoxy)hexan-1-ol                                                                          0.25   kg                                            Polysorbate 80 (Polyoxyethylene (20)                                                                   0.25   kg                                            sorbitan mono-oleate)                                                         Corn Oil sufficient to make                                                                            25.0   kg                                            ______________________________________                                    

Mix and fill into 50,000 soft gelatin capsules.

What is claimed is:
 1. A method of treating a retroviral infection in a patient in need thereof which comprises administering to said patient an anti-retrovirally effective amount of a compound of the formula:

    Ar--O(CH.sub.2).sub.n OH

wherein n is an integer from 3 to 8 and Ar is phenyl or phenyl substituted by from 1 to 3 C₁₋₄ lower alkyl groups, an ester thereof with a C₁₋₄ alkanoic, alkenoic , alkanedioic or alkenedioic acid having from 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof.
 2. A method according to claim 1 wherein n is
 6. 3. A method according to claim 1 wherein AR is phenyl.
 4. A method according to claim 1 wherein the compound is 6-phenoxyhexan-1-ol, an ester thereof with a C₁₋₄ alkanoic, alkenoic, alkanedioic or alkenedioic acid having from 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof.
 5. A method according to claim 4 wherein the compound is 6-phenoxyhexan-1-ol.
 6. A method according to claim 1 wherein the compound is 6-(2,4,6-trimethylphenoxy)hexan-1-ol, an ester thereof with a C₁₋₄ alkanoic, alkenoic, alkanedioic or alkenedioic acid having from 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof.
 7. A method according to claim 6 wherein the compound is 6-(2,4,6-trimethylphenoxy)hexan-1-ol. 